XIAP antisense oligonucleotide (AEG35156) achieves target knockdown and induces apoptosis preferentially in CD34⁺38⁻ cells in a phase 1/2 study of patients with relapsed/refractory AML

• Published in: Apoptosis (London) Vol. 16; no. 1; pp. 67 - 74
• Main Authors: Carter, Bing Z, Mak, Duncan H, Morris, Stephen J, Borthakur, Gautam, Estey, Elihu, Byrd, Anna L, Konopleva, Marina, Kantarjian, Hagop, Andreeff, Michael
• Format: Journal Article
• Language: English
• Published: Boston Boston : Springer US 2011; Springer US
• Subjects: Aged; AML; Antigens, CD - analysis; Antigens, CD - drug effects; Antimetabolites, Antineoplastic - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antisense oligonucleotide AEG35156; apoptosis; Apoptosis - drug effects; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cancer Research; Caspases - metabolism; Cell Biology; Clinical trial; Cytarabine - administration & dosage; Drug Administration Schedule; Drug Dosage Calculations; Female; Gene Expression - drug effects; Humans; Idarubicin - administration & dosage; Leukemia, Myeloid, Acute - drug therapy; Male; Middle Aged; Myeloid Progenitor Cells - cytology; Myeloid Progenitor Cells - metabolism; Oligonucleotides - administration & dosage; Oncology; Original Paper; Recurrence; RNA, Messenger - biosynthesis; Virology; X-Linked Inhibitor of Apoptosis Protein - antagonists & inhibitors; X-Linked Inhibitor of Apoptosis Protein - genetics; XIAP; AML; XIAP; Clinical trial; Antisense oligonucleotide AEG35156; Apoptosis
• ISSN: 1360-8185; 1573-675X
• DOI: 10.1007/s10495-010-0545-1

XIAP, a potent caspase inhibitor, is highly expressed in acute myeloid leukemia (AML) cells and contributes to chemoresistance. A multi-center phase 1/2 trial of XIAP antisense oligonucleotide AEG35156 in combination with idarubicin/cytarabine was conducted in 56 patients with relapsed/refractory AML. Herein we report the pharmacodynamic studies of the patients enrolled at M. D. Anderson Cancer Center. A total of 13 patients were enrolled in our institution: five in phase 1 (12-350 mg/m² AEG35156) and eight in phase 2 (350 mg/m² AEG35156) of the protocol. AEG35156 was administered on 3 consecutive days and then weekly up to a maximum of 35 days. Blood samples were collected from patients on days 1 through 5 and on day 28-35 post-chemotherapy for detection of XIAP levels and apoptosis. AEG35156 treatment led to dose-dependent decreases of XIAP mRNA levels (42-100% reduction in phase 2 patients). XIAP protein levels were reduced in all five samples measured. Apoptosis induction was detected in 1/4 phase 1 and 4/5 phase 2 patients. Importantly, apoptosis was most pronounced in CD34 ⁺ 38 ⁻ AML stem cells and all phase 2 patients showing apoptosis induction in CD34 ⁺ 38 ⁻ cells achieved response. We conclude that at 350 mg/m², AEG35156 is effective in knocking down XIAP in circulating blasts accompanied by the preferential induction of apoptosis in CD34 ⁺ 38 ⁻ AML stem cells.